Angiogenesis is essential in the female reproduction system and during development and wound repair. However, inappropriate angiogenesis can have severe consequences. Indeed, the proliferation of new blood vessels from pre-existing capillaries plays a key role in diseases, such as the pathological development of solid tumor cancers, solid tumor metastases, angiofibromas, skin cancer, retrolental fibroplasia, Kaposi's sarcoma, childhood hemangiomas, diabetic retinopathy, neovascular glaucoma, age related macular degeneration, psoriasis, gingivitis, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, and capillary proliferation in atherosclerotic plaques. Because these serious diseases afflict several million people in the United States each year, considerable scientific effort has been directed toward gaining an understanding of the mechanisms regulating angiogenesis and toward developing therapies for such diseases.
With respect to cancer, over six hundred thousand new cases of lung, colon, breast and prostate cancer will be diagnosed in the United States each year, accounting for 75% of new solid tumor cancers and 77% of solid tumor cancer deaths. Although advances in therapy and in our understanding of cancer causes and risk factors have lead to improved outcomes overall, most cancers still have low five year survival rates. Despite these advances in primary tumor management, 50% of patients will ultimately die of their disease largely due to side effects of current therapies or to the metastatic spread of tumors to numerous or inoperable sites through the tumor associated vasculature. It is now known that the growth and spread of solid tumor cancer depends on the development of a tumor-associated vasculature by a process known as angiogenesis.
One of the most significant consequences of tumor angiogenesis is the invasion of tumor cells into the vasculature. Thus, vascularization permits the survival and growth of primary tumors, as well as the metastatic spread of cancer. Metastases arise from tumor cells which enter the tumor's own vasculature to be carried to local and distant sites where they create new tumors. Tumors have typically established a vasculature and metastasized to local and distant sites by the time that primary tumors are detectable.
Current treatments for cancer rely mainly on treatments which are not selective for the disease but which have deleterious effects on other organs of the body. For example, chemotherapeutics reagents or radiation have serious side effects because they kill or impair all proliferating cells in the body, including healthy cells. Side effects are unpleasant and often create health problems that themselves increase patient mortality.
Angiogenesis also plays a major role in the progression and exacerbation of a number of inflammatory diseases. Psoriasis, a disease which afflicts 2 million Americans, is characterized by significant angiogenesis. In rheumatoid arthritis and possibly osteoarthritis, the influx of lymphocytes into joints induces blood vessels of the joint synovial lining to undergo angiogenesis; this angiogenesis appears to permit a greater influx of leukocytes and the destruction of cartilage and bone. Angiogenesis is also likely to play a role in chronic inflammatory diseases such as ulcerative colitis and Crohn's disease. In addition, the growth of capillaries into atherosclerotic plaques is a serious problem; the rupture and hemorrhage of vascularized plaques is thought to cause coronary thrombosis. To date, however, no effective therapies exist for these diseases.
Angiogenesis is also a factor in many ophthalmic disorders which can lead to blindness. In age-related macular degeneration (ARMD), a disorder afflicting 25% of otherwise healthy individuals over the age of 60, and in diabetic retinopathy, a condition prevalent among both juvenile and late onset diabetics, angiogenesis is induced by hypoxic conditions on the choroid or the retina, respectively. Hypoxia induces an increase in the secretion of growth factors including vascular endothelial growth factor (VEGF). It is possible that VEGF expression in the eye induces the migration and proliferation of endothelial cells into regions of the eye where they are not ordinarily found. Vascularization in ocular tissue has adverse effects on vision. New blood vessels on the cornea can induce corneal scarring, whereas new blood vessels on the retina can induce retinal detachment, and angiogenic vessels in the choroid may leak vision-obscuring fluids; these events often lead to blindness.
For other pathological conditions associated with abnormal angiogenesis such as diabetic retinopathy, there are no effective treatments short of retinal transplants. However, even in cases where retinal transplantation is performed, the new retina is subject to the same conditions that resulted in the original retinopathy.
While agents that prevent continued angiogenesis are currently being tested, there remains a need to identify the molecular interactions involved in the undesirable angiogenesis that occurs in certain pathological conditions, and to develop methods for diagnosing and specifically treating such pathologies.